Abstract
AbstractDTNBP1 (dystrobrevin binding protein 1) remains one of the top candidate genes in schizophrenia. Reduced expression of this gene and the protein it encodes, dysbindin-1, has been reported in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia cases. It has not been established, however, if all dysbindin-1 isoforms are reduced in the DLPFC or if the reduction is associated with reduced DTNBP1 gene expression. Using Western blotting of whole-tissue lysates of the DLPFC with antibodies differentially sensitive to the three major isoforms of this protein (dysbindin-1A, -1B, and -1C), we found no significant differences between our schizophrenia cases and matched controls in dysbindin-1A or -1B, but did find a mean 46% reduction in dysbindin-1C in 71% of 28 case-control pairs (p = 0.022). This occurred in the absence of the one DTNBP1 risk haplotype for schizophrenia reported in the US and without alteration in levels of dysbindin-1C transcripts. Conversely, the absence of changes in the dysbindin-1A and -1B isoforms was accompanied by increased levels of their transcripts. We thus found no correspondence between alterations in dysbindin-1 gene and protein expression, the latter of which might be due to posttranslational modifications such as ubiquitination. Reduced DLPFC dysbindin-1C in schizophrenia probably occurs in PSDs, where we find dysbindin-1C to be heavily concentrated in the human brain. Given known postsynaptic effects of dysbindin-1 reductions in the rodent homolog of the prefrontal cortex, these findings suggest that reduced dysbindin-1C in the DLPFC may contribute to cognitive deficits of schizophrenia by promoting NMDA receptor hypofunction.
Highlights
Using Western blotting of whole-tissue lysates of the dorsolateral prefrontal cortex (DLPFC) with antibodies differentially sensitive to the three major isoforms of this protein, we found no significant differences between our schizophrenia cases and matched controls in dysbindin-1A or -1B, but did find a mean 46% reduction in dysbindin-1C in 71% of 28 case-control pairs (p = 0.022)
Given known postsynaptic effects of dysbindin-1 reductions in the rodent homolog of the prefrontal cortex, these findings suggest that reduced dysbindin-1C in the DLPFC may contribute to cognitive deficits of schizophrenia by promoting NMDA receptor hypofunction
Dysbindin-1 Isoforms in DLPFC According to NCBI’s Reference Sequence (RefSeq) database, a highly curated transcript collection,[42] there are three validated splice variants of human DTNBP1 mRNA among sixteen deduced DTNBP1 splice variants identified in the AceView database
Summary
Since the initial report of Straub et al in 2002,1 many studies have found that genetic variation in DTNBP1 (dystrobrevin binding protein 1) is associated with schizophrenia as reviewed by several investigators.[2,3,4] DTNBP1 remains among the top candidate genes for the disorder according to recent analyses.[5,6] DTNBP1 risk SNPs and haplotypes have been associated with a diverse group of cognitive deficits, which collectively form a core feature of schizophrenia.[7,8,9] Even in individuals without psychiatric illness, cognitive performance is worse in carriers of DTNBP1 risk SNPs than in non-carriers.[10,11,12] The same is true for Sz cases carrying such SNPs. Since the initial report of Straub et al in 2002,1 many studies have found that genetic variation in DTNBP1 (dystrobrevin binding protein 1) is associated with schizophrenia as reviewed by several investigators.[2,3,4] DTNBP1 remains among the top candidate genes for the disorder according to recent analyses.[5,6] DTNBP1 risk SNPs and haplotypes have been associated with a diverse group of cognitive deficits, which collectively form a core feature of schizophrenia.[7,8,9] Even in individuals without psychiatric illness, cognitive performance is worse in carriers of DTNBP1 risk SNPs than in non-carriers.[10,11,12] The same is true for Sz cases carrying such SNPs They show greater decline in general cognitive ability from a premorbid to a clinical state,[13] lower general cognitive ability in the clinical state itself,[10] lower scores on verbal, performance, and full-scale IQ tests on the Wechsler Adult Intelligence Scales-Revised,[14, 15] deficits on a spatial working memory task and a Go NoGo attentional response task,[16] and poor performance on Trail-Making Tests A and B.17
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